This invention relates to the synthesis of 2,4,6-triiodo-5-amino-N-alkylisophthalamic acid and 2,4,6-triiodo-5-amino-isophthalamide compounds, and more particularly, to an improved process for enhancing yields and improving the quality of the iodinated products.
2,4,6-triiodo-5-amino-N-alkylisophthalamic acid, or a salt or ester thereof, is a useful intermediate in the manufacture of X-ray contrast media. As described, for example, in Hoey U.S. Pat. No. 3,145,197, 5-acetamido-N-alkyl-2,4,6-triiodoiosphthalamic acid compounds are produced by treatment of 2,4,6-triiodo-5-amino-N-isophthalamic acid with an acylating agent such as a lower acyl halide or a lower alkanoic acid in the presence of a catalyst such as sulfuric acid or perchloric acid. In accordance with the scheme described in the Hoey patent, 5-nitroisophthalic acid is first converted to its dialkyl ester and one of the ester groups is then selectively hydrolyzed by careful treatment in a suitable solvent with one equivalent of a strong base such as sodium or potassium hydroxide. The monoester is reacted with a primary lower alkylamine to produce 5-nitro-N-alkylisophthalamic acid and the latter intermediate is subjected to catalytic hydrogenation to produce 5-amino-N-alkylisophthalamic acid commonly referred to as the "reduced half amide" or "RHA".
The RHA is triiodinated by reaction with a source of an iodine halide, preferably a source of iodine monochloride such as potassium iododichloride (KICl.sub.2). In accordance with the Hoey process, the iodination reaction is effected with a modest net excess of iodinating agent, typically in hydrochloric acid solution. However, while the net overall charge of iodinating agent is in excess, the Hoey process involves first charging all or a substantial portion of the RHA to an aqueous reaction medium, and then adding the iodinating agent over a period of time. Thus, throughout most of the reaction period, there is a substantial excess of RHA in the reaction zone. In one embodiment described by Hoey, the entire RHA charge is first dissolved in a hydrochloric acid medium and the iodinating agent thereafter added thereto. In another embodiment, RHA is first reacted with less than a stoichiometrically equivalent amount of potassium iododichloride in aqueous suspension and, after several hours, sodium hydroxide and the remainder of the potassium iododichloride are added and reaction carried to completion.
The product of the reaction has generally been found to contain a fraction of mono- and di-iodinated species, thereby detracting from both product yield and product quality.
Because the RHA is typically dissolved in a hydrochloric acid medium preparatory to the addition of the iodinating agent, and because hydrochloric or other hydrogen halide acid is, in any event, a product of the reaction, the methods previously known to the art have involved conducting at least a substantial portion of the reaction at acid concentrations sufficiently high that the pH of the reaction medium is negative. Such pH conditions inhibit the progress of the reaction, thus requiring the use of an ultimate excess of the iodine halide source to drive the reaction to completion. Since the iodine halide source is not practicably recoverable from the reaction medium, the excess is effectively lost, with a resultant adverse impact on manufacturing cost. Moreover, even with an excess of iodinating reagent, the reaction is not always driven fully to completion so that the quality of the product may be less than desired.
As the reaction between RHA and iodinating agent progresses, the iodinated product compound precipitates from the reaction mixture as a crystalline solid. Acidification at the end of the reaction period precipitates the triiodo product remaining in solution. This product is recovered from the reaction mass by filtration or centrifugation. The purity of iodinated reaction product and yield obtained thereof are dependent on the efficiency of this separation. In the conventional process, some difficulty has been experienced with effective separation of the product crystals from the reaction medium mother liquor. This has detracted from the yield commercially achievable in the manufacture of X-ray contrast media from the 2,4,6-triiodo-5-amino-N-alkylisophthalamic acid produced by iodination of RHA.
Similarly, the compound 5-amino-N,N'-bis(2,3-dihydroxy-propyl)-2,4,6-triiodoisophthalamide is an intermediate in the preparation of N,N'-bis(2,3-dihydroxy-propyl)-5[N-(2-hydroxyethyl)glycolamido]-2,4,6-trii odoisophthalamide. The latter compound is a nonionic x-ray contrast agent (see Lin U.S. Pat. No. 4,396,598).
Heretofore, it has been known to prepare 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide from 5-amino-N,N'-bis(2,3-dihydroxypropyl)isophthalamide (known as the "reduced diamide") by acidifying an aqueous reaction medium containing the latter compound with 30% hydrochloric acid to a pH of 0.9-1.0, heating the resulting solution to a temperature of approximately 81.degree.-84.degree. C. and adding an iodine monochloride aqueous solution over a period of 3/4 to 1 hour. The solution is then stirred and heated at a temperature of 81.degree.-84.degree. C. for 3 to 4 hours. After the reaction is completed, the solution is cooled to 55.degree.-60.degree. C. and sodium bisulfite is added to destroy excess iodine and/or iodine monochloride. The solution is then cooled to approximately 25.degree. C. and sodium hydroxide solution is added slowly at 25.degree.-40.degree. C. to adjust the pH to 4-7. After seeding with 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisopthalamide, the solution is cooled to 0.degree.-5.degree. C. and stirred to effect precipitation of the desired product, 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide.
The above-described process suffers from certain shortcomings. It undesirably produces a product containing impurities which may be hydrolysis products and also containing a small amount of uniodinated reduced amide. Moreover, the reaction between the reduced amide and iodine monochloride produces so much HCl that the pH of the reaction medium falls below 0 and undesirably retards the desired reaction and reduces the yield of the desired product.
There has been a need in the art for an improved process which affords improved yields and produces a higher purity 2,4,6-triiodo-5-amino-N-alkylisophthalamic acid product or 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide or other 2,4,6-triiodo-5-aminoisophthalamide compound.